Fewer systematic prostate core biopsies in clinical stage T1c prostate cancer leads to biochemical recurrence after brachytherapy as monotherapy.

BACKGROUND: After brachytherapy, fewer prostate biopsy cores at diagnosis can underestimate the pathological characteristics of prostate cancer (PCa) with lower concordance, resulting in improper treatment, particularly in patients with low-risk nonpalpable cT1c PCa. The aim of this study was to assess the relationship between the number of biopsy cores at diagnosis and long-term clinical outcomes after brachytherapy for cT1c PCa. METHODS: We reviewed 516 patients with localized cT1c PCa with Gleason scores of 3 + 3 = 6 or 3 + 4 = 7 who underwent brachytherapy as monotherapy without hormonal therapy between January 2005 and September 2014 at our institution. Clinical staging was based on the American Joint Committee on Cancer manual for staging. Thus, the cT1c category is based solely on digital rectal examination. The primary outcome was biochemical recurrence (BCR). Based on the optimized cutoff value for biopsy core number obtained from receiver operating characteristic analysis, patients were divided into the biopsy cores ≤8 (N = 123) and ≥9 (N = 393) groups. The BCR-free survival rate was compared between the groups. Prognostic factors for BCR were evaluated, including age, initial prostate-specific antigen (PSA) level, Gleason score, positive core rate, PSA density, prostate magnetic resonance imaging findings, and biopsy core number. RESULTS: The median patient age was 66.0 years (interquartile range [IQR]: 61.0-71.0 years), and the median follow-up time was 11.1 years (IQR: 9.5-13.3 years). The median number of core biopsies was 12 (IQR: 9-12). The area under the curve was 0.637 (95% confidence interval [CI]: 0.53-0.75), and the optimal biopsy core cutoff value for BCR prediction was 8.5 (sensitivity = 43.5%, specificity = 77.1%). Although fewer patients had Gleason scores of 3 + 4 = 7 (19/123 [15%] vs. 125/393 [32%], p < 0.02) in the biopsy cores ≤8 group, the 10-year BCR-free survival rate was significantly lower in the biopsy cores ≤8 group than in the biopsy cores ≥9 group (93.8% vs. 96.3%, p < 0.05). Multivariate analysis revealed that a lower biopsy core number (hazard ratio: 0.828, 95% CI: 0.71-0.97, p < 0.03) and a Gleason score of 3 + 4 = 7 (hazard ratio: 3.26, 95% CI: 1.37-7.73, p < 0.01) significantly predicted BCR. CONCLUSIONS: A low number of prostate core biopsies results in worse BCR-free survival after brachytherapy as monotherapy in patients with cT1c PCa.

Secondary bladder cancer during long-term follow-up after iodine-125 permanent seed implantation for localized prostate cancer.

INTRODUCTION: Brachytherapy for prostate cancer treatment may induce secondary bladder cancer during long-term follow-ups. This study reviews the risk and tumor characteristics of secondary bladder cancer after brachytherapy. METHODS: This single-institution retrospective study included 1162 patients treated with low-dose-rate permanent seed implantation brachytherapy with iodine-125, with or without external beam radiation therapy, for localized prostate cancer. We calculated and compared the rates of secondary bladder cancer among patients treated with brachytherapy and radical prostatectomy (n = 218) before and after a propensity score-matching analysis. Possible risk factors for secondary bladder cancer, such as patient age and external beam radiation therapy administration, were analyzed. RESULTS: Of 1162 patients with a median follow-up period of 11.4 (range: 0.7-15.5) years, 26 presented with urothelial carcinomas and 1 with adenocarcinoma at a median of 8.9 (range: 2.9-14.0) years after brachytherapy, although the incidence rates of secondary bladder cancer after brachytherapy were not significantly different from those after radical prostatectomy. No significant risk factors for secondary bladder cancer were identified. The initial symptoms of secondary bladder cancer were gross hematuria (74%) and microscopic hematuria with positive urine cytology (15%). Among 26 cases of secondary urothelial carcinoma, 54% were high-grade and 46% were invasive. After brachytherapy, invasive urothelial carcinoma occurred later than noninvasive urothelial carcinoma (p = 0.01). CONCLUSIONS: Considering the aggressive malignancy of secondary bladder cancer, cystoscopy and urine cytology should be performed for further investigation of the causes of gross or microscopic hematuria and rule out secondary bladder cancer in cases followed longer than 3 years after brachytherapy.

A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH, NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs.

Effect of adding androgen deprivation therapy to permanent iodine-125 implantation with or without external beam radiation therapy on the outcomes in patients with intermediate-risk prostate cancer: A propensity score-matched analysis.

PURPOSE: The purpose of the study was to evaluate the effect of adding androgen deprivation therapy (ADT) to brachytherapy with or without external beam radiation therapy on oncological outcomes in prostate cancer. METHODS AND MATERIALS: Overall, 1,171 patients with intermediate-risk prostate cancer treated with brachytherapy with or without external beam radiation therapy with or without ADT between 2003 and 2013 were identified. Propensity score matching was used to counter biases between the ADT and non-ADT groups. The biochemical failure-free rate (bFFR), local recurrence-free rate, and overall survival rate were evaluated using Kaplan-Meier curves, and predictors were identified using Cox proportional hazards regression models. RESULTS: After propensity score matching, 405 patients were included in each group. The median followup duration was 9.1 years; the median ADT duration was 6 months. In the ADT versus non-ADT groups, the 9-year bFFR, local recurrence-free rate, and overall survival rate were 93.4% versus 87.8% (p = 0.016), 96.9% versus 98.1% (p = 0.481), and 88.1% versus 90.4% (p = 0.969), respectively. On multivariate analyses, Gleason score (hazard ratio [HR]: 2.52, 95% confidence interval [CI]: 1.58-4.03) and ADT use (HR: 0.55, 95% CI: 0.34-0.89) were associated with biochemical failure. Supplemental external beam radiation therapy use (HR: 0.38, 95% CI: 0.16-0.91) was associated with lower local recurrence rates. Age (HR: 1.12, 95% CI: 1.08-1.16) and comorbidities (HR: 1.56, 95% CI: 1.04-2.34) were associated with all-cause mortality. CONCLUSIONS: A risk-benefit assessment between bFFR improvement and the potential side effects of adding ADT to brachytherapy-based radiotherapy is warranted before incorporating ADT as routine practice.

Whole-gland salvage treatment for recurrent prostate cancer after initial definitive radiotherapy: A case series of 125I brachytherapy and robot-assisted radical prostatectomy.

PURPOSE: To analyze outcomes following whole-gland salvage treatments applied to patients with pathology-proven, locally recurrent prostate cancer following primary definitive radiotherapy. MATERIAL AND METHODS: Eighteen consecutive patients who received whole-gland salvage treatments at our institution were retrospectively reviewed. All patients underwent transperineal template-guided mapping biopsy (TTMB) using the standard iodine-125 (125I) brachytherapy (BT) setup. Twelve patients received 125I BT, and six patients underwent robot-assisted laparoscopic prostatectomy (RARP). Prostate-specific antigen (PSA) failure was determined using the Phoenix definition (nadir + 2 ng/ml) following BT and a PSA level of > 0.2 ng/ml following RARP. Toxicities were graded according to CTCAE version 4.0. RESULTS: The median follow-up times were 71 and 11 months for the BT and RARP groups, respectively. In the BT group, the median dose to 90% of the prostate was 131 Gy. The median time to biochemical failure was 47 months, and the biochemical relapse-free survival (BRFS) rates were 56% (95% confidence interval [CI]: 33-94%) and 46% (95% CI: 25-88%) at 3 years and 5 years, respectively. Four patients (33%) developed grade 2 genitourinary (GU) toxicity, and two (17%) developed grade 3 GU toxicity. No patients developed grade ≥ 2 gastrointestinal (GI) toxicity. In the RARP group, three out of six patients (50%) had PSA failure, and four patients (67%) developed grade 2 GU toxicity. No patients developed grade 3 GU toxicity or grade ≥ 2 GI toxicity. On pre-salvage magnetic resonance imaging (MRI), no patients were suspected of having T3 or higher stage lesions. However, three patients (50%) had pT3a and two patients (33%) had pT3b (i.e., seminal vesicle invasion) stage lesions. CONCLUSIONS: Whole-gland salvage BT is an effective treatment with an acceptable toxicity profile. The pathology findings from RARP imply that there is a room for improvement in diagnoses made by MRI in the pre-salvage setting.

Selection of patients who would not require long-term prostate-specific antigen monitoring after low-dose-rate brachytherapy.

PURPOSE: To identify patients at extremely low risk of biochemical recurrence (BCR) of prostate cancer after low-dose-rate brachytherapy (LDR-BT) to determine when prostate-specific antigen (PSA) monitoring can be stopped. METHODS AND MATERIALS: We retrospectively reviewed clinicopathologic data of patients with prostate cancer who underwent LDR-BT between 2003 and 2011. Of 1569 patients reviewed, 689 (43.9%) received combination external beam radiotherapy, and 970 (61.8%) had neoadjuvant hormonal therapy. We stratified patients according to risk factors identified by multivariate analysis and assessed the factors for an association with BCR (defined as ≥2 ng/mL higher than the nadir). RESULTS: The median followup was 96 months. Of 1531 patients who were BCR-free at 3 years after treatment, 76 subsequently developed BCR; of 1500 who were BCR-free at 5 years, 45 eventually had BCR. On multivariate analysis, independent risk factors for BCR were the National Comprehensive Cancer Network risk group at diagnosis and PSA levels at 3 or 5 years after radiotherapy. In the low-risk group, no patient with a PSA level ≤0.2 ng/mL at 3 years after radiotherapy subsequently developed BCR. In the intermediate-risk group, no patients with a PSA level ≤0.2 ng/mL at 5 years subsequently developed BCR. CONCLUSIONS: The National Comprehensive Cancer Network risk group at diagnosis and PSA values at 3 and 5 years after LDR-BT are independently associated with a risk of later BCR. Using these two factors may help to select patients for whom PSA monitoring could be stopped because they have an extremely low risk of later BCR.

Predictive factors of long-term rectal toxicity following permanent iodine-125 prostate brachytherapy with or without supplemental external beam radiation therapy in 2216 patients.

PURPOSE: We analyzed factors associated with rectal toxicity after iodine-125 prostate brachytherapy (BT) with or without external beam radiation therapy (EBRT). METHODS AND MATERIALS: In total, 2216 prostate cancer patients underwent iodine-125 BT with or without EBRT between 2003 and 2013. The median followup was 6.9 years. Cox proportional hazards modeling was used for univariate and multivariate analyses to assess clinical and dosimetric factors associated with rectal toxicity. Dosimetric parameters from 1 day after implantation (Day 1) and 1 month after implantation (Day 30) were included in the analyses. RESULTS: The 7-year cumulative incidence of Grade 2 or higher rectal toxicity was 5.7% in all patients. The multivariate analysis revealed that antiplatelet or anticoagulant therapy, neoadjuvant androgen deprivation therapy, treatment modality, Day 1 rectal volume receiving 100% of the prescribed dose (RV100), and the Day 30 minimal percent of the prescribed dose delivered to 30% of the rectum (RD30) were associated with rectal toxicity. Day 1 RV100 was a common predictor in both BT-alone and the BT + EBRT groups. The 5-year cumulative incidence of Grade 2 or higher rectal toxicity was 12.6%, 5.9%, and 1.7% for BT + 3-dimensional conformal radiation therapy, BT + intensity-modulated radiation therapy, and the BT-alone groups, respectively (p < 0.001). CONCLUSIONS: Rectal dosimetric parameters in BT were associated with late rectal toxicity. Although the risk of rectal toxicity was higher when EBRT was combined with BT, with proper and achievable rectal dose constraints intensity-modulated radiation therapy yielded less toxicity than 3-dimensional conformal radiation therapy.

The Initial Case Report: Salvage Robotic Assisted Radical Prostatectomy After Heavy Ion Radiotherapy.

Salvage radical prostatectomy is one of treatments after radiation therapy to patients with prostate cancer. To date, no case of the salvage robotic assisted radical prostatectomy (RARP) following heavy ion radiotherapy (HIRT) has been published. We report on a 70-year-old man with a history of HIRT for prostate cancer in 2011. For 3 years after. HIRT, his serum PSA levels were permissible range. However, his PSA levels were increased. We had diagnosis localized prostate cancer after HIRT. We had carried out salvage RARP. Until 10 months after salvage RARP, his PSA level was not detectable.

Predictive factors for urinary toxicity after iodine-125 prostate brachytherapy with or without supplemental external beam radiotherapy.

PURPOSE: We examined the factors associated with urinary toxicities because of brachytherapy with iodine-125 with or without supplemental external beam radiotherapy (EBRT) for prostate cancer. METHODS AND MATERIALS: We investigated 1313 patients with localized prostate cancer treated with iodine-125 brachytherapy with or without supplemental EBRT between 2003 and 2009. The International Prostate Symptom Score (IPSS) and Common Terminology Criteria for Adverse Events data were prospectively determined. Patients, treatment, and implant factors were investigated for their association with urinary toxicity or symptoms. RESULTS: IPSS resolution was not associated with biologically effective dose (BED). Baseline IPSS, total needles, and the minimal dose received by 30% of the urethra had the greatest effect according to multivariate analysis (MVA). Urinary symptom flare was associated with baseline IPSS, age, BED, and EBRT on MVA. Urinary symptom flare and urinary Grade 2 or higher (G2+) toxicity occurred in 51%, 58%, and 67% (p = 0.025) and 16%, 22%, and 20% (p = 0.497) of the <180, 180-220, and >220 Gy BED groups, respectively. Urinary G2+ toxicity was associated with baseline IPSS, neoadjuvant androgen deprivation therapy (NADT), and seed density on MVA. When we divided patients into four groups according to prostate volume (<30 cc or ≥30 cc) and NADT use, urinary G2+ toxicity was most commonly observed in those patients with larger prostates who received NADT, and least in the patients with smaller prostates and no NADT. CONCLUSIONS: NADT was associated with urinary G2+ toxicity. Higher dose and supplemental EBRT did not appear to increase moderate to severe urinary toxicities or time to IPSS resolution; however, it influenced urinary symptom flare.

Schmorl Nodes Mimicking Osteolytic Bone Metastases.

Bone is the third most common site of metastasis from upper tract urothelial carcinoma after radical nephroureterectomy. Although bone biopsy is the gold standard for the diagnosis of bone metastases, they can usually be diagnosed on the basis of imaging tests. We describe a case of upper tract urothelial carcinoma after radical nephroureterectomy presenting with a Schmorl node in the third lumbar vertebra, mimicking lytic bone metastasis. Differentiation of bone metastases from Schmorl nodes is essential for the appropriate management of patients with malignancy.

Permanent prostate brachytherapy with or without supplemental external beam radiotherapy as practiced in Japan: outcomes of 1300 patients.

PURPOSE: To report outcomes for men treated with iodine-125 ((125)I) prostate brachytherapy (BT) at a single institution in Japan. METHODS AND MATERIALS: Between 2003 and 2009, 1313 patients (median age, 68 years) with clinically localized prostate cancer were treated with (125)I BT. Median prostate-specific antigen level was 7.6 ng/mL (range, 1.1-43.3). T-stage was T1c in 60%, T2 in 39%, and T3 in 1% of patients. The Gleason score was <7, 7, and >7 in 49%, 45%, and 6% of patients, respectively. Neoadjuvant androgen deprivation therapy was used in 40% of patients and combined external beam radiotherapy of 45 Gy in 48% of patients. Postimplant dosimetry was performed after 30 days after implantation, with total doses converted to the biologically effective dose. Survival functions were calculated by the Kaplan-Meier method and Cox hazard model. RESULTS: Median followup was 67 months (range, 6-126). The 7-year biochemical freedom from failure for low-, intermediate-, and selected high-risk prostate cancers were 98%, 93%, and 81%, respectively (p < 0.001). Multivariate analysis identified the Gleason score, initial prostate-specific antigen level, positive biopsy rate, dose, and neoadjuvant androgen deprivation therapy as predictors for biochemical freedom from failure. The 7-year actuarial developing Grade 3+ genitourinary and gastrointestinal toxicity was 2% and 0.3%, respectively. Forty-four percent patients with normal baseline potency retained normal erectile function at 5 years. CONCLUSIONS: (125)I prostate BT is a highly effective treatment option for low-, intermediate-, and selected high-risk prostate cancers. Side effects were tolerable. An adequate dose may be required to achieve successful biochemical control.

A dose-response analysis of biochemical control outcomes after (125)I monotherapy for patients with favorable-risk prostate cancer.

PURPOSE: To define the optimal dose for (125)I prostate implants by correlating postimplantation dosimetry findings with biochemical failure and toxicity. METHODS AND MATERIALS: Between 2003 and 2009, 683 patients with prostate cancer were treated with (125)I prostate brachytherapy without supplemental external beam radiation therapy and were followed up for a median time of 80 months. Implant dose was defined as the D90 (the minimal dose received by 90% of the prostate) on postoperative day 1 and 1 month after implantation. Therefore, 2 dosimetric variables (day 1 D90 and day 30 D90) were analyzed for each patient. We investigated the dose effects on biochemical control and toxicity. RESULTS: The 7-year biochemical failure-free survival (BFFS) rate for the group overall was 96.4% according to the Phoenix definition. A multivariate analysis found day 1 D90 and day 30 D90 to be the most significant factors affecting BFFS. The cutoff points for day 1 D90 and day 30 D90, calculated from ROC curves, were 163 Gy and 175 Gy, respectively. By use of univariate analysis, various dosimetric cutoff points for day 30 D90 were tested. We found that day 30 D90 cutoff points from 130 to 180 Gy appeared to be good for the entire cohort. Greater D90s were associated with an increase in late genitourinary or gastrointestinal toxicity ≥ grade 2, but the increase was not statistically significant. CONCLUSIONS: Improvements in BFFS rates were seen with increasing D90 levels. Day 30 D90 doses of 130 to 180 Gy were found to serve as cutoff levels. For low-risk and low-tier intermediate-risk prostate cancer patients, high prostate D90s, even with doses exceeding 180 Gy, achieve better treatment results and are feasible.

Five-year potency preservation after iodine-125 prostate brachytherapy.

BACKGROUND: We aimed to evaluate long-term erectile function following prostate brachytherapy, based on patient characteristics and treatment factors. METHODS: Between 2003 and 2006, 665 men with localized prostate cancer were treated with (125)I permanent seed implantation. None was given adjuvant hormone therapy. Erectile function was assessed before treatment, and at 6 months, 1, 2, 3, 4 and 5 years after implantation using the Mount Sinai Erectile Function Score (MSEFS) of 0-3 (0 = no erections, 1 = erections insufficient for intercourse, 2 = suboptimal erections but sufficient for intercourse, 3 = normal erectile function). Potency was defined as score 2 or 3, and 382 men were potent before treatment. Univariate and multivariate analyses were performed on the data from these 382 patients to identify variables associated with potency preservation. RESULTS: In patients who were potent before treatment, the actuarial potency preservation rate fell to 46.2 % at 6 months after brachytherapy, and then slowly recovered reaching 52.0 % at 5 years after brachytherapy. In multivariate logistic regression analysis, patient age (p = 0.04) and pre-treatment MSEFS (p < 0.001) were predictors of 5-year potency preservation. Neoadjuvant hormone therapy affected potency preservation only at 6 months after brachytherapy. CONCLUSIONS: Patient age at implantation and pre-treatment erectile function are predictive factors for the development of erectile dysfunction following prostate brachytherapy.

[Sexual function after permanent seed implant prostate brachytherapy].

PURPOSE: The aim of this study was to evaluate the long-term effects of permanent seed implant prostate brachytherapy (BT) on sexual function (SF). MATERIALS AND METHODS: From September 2003 to July 2005, 56 patients underwent radical retropubic prostatectomy (RRP) without any hormone therapy, while 353 patients had undergone BT without any adjuvant hormone therapy in a single institute. Out of these 353 patients in the BT group, 305 patients received neoadjuvant hormone therapy (BT NHT + group), while 48 did not (BT NHT - group). SF was prospectively evaluated using the UCLA Prostate Cancer Index (UCLA-PCI). Potency was defined as the UCLA-PCI Q26 point of > or = 3. RESULT: The preimplant UCLA-PCI scores of SF for BT NHT - and BT NHT + groups were 50.9 and 13.4, respectively. The SF score of the NHT - group post operatively decreased to 38.9 within 6 months, but was maintained at the same level after that. With the recovery of the androgen, SF score of the NHT + group improved after BT: however, it did not reach up to that of the NHT - group. In the univariate analysis, patient's age was the only predictive factor for SF after BT. Thirty-four out of 48 patients in the BT NHT - group and 23 out of 56 patients in the RRP group showed adequate potency before surgery. Their 5-year potency preservation rate was 73.6% in the BT NHT - group and 4.3% in the RRP group. CONCLUSION: SF slightly decreased immediately after BT but was usually maintained during the course observation for 5 years. The 5-year SF preservation rate after BT was 73.6%.

[Two cases of bowel perforation in patients with metastatic renal cancer treated with a molecularly targeted drug].

(Case 1) An 82-year-old man started immunotherapy with interferon because of lung metastasis 5 years after he had undergone radical nephrectomy. Three years later, he developed multiple metastases, and was started on sorafenib (400 mg/day) and nonsteroidal anti-inflammatory drug (NSAID) orally. As his cancer-related pain worsened with time, he was administered 30 Gy radiation therapy for bone metastasis of L4. He was then admitted to our hospital for pain control because of ineffective radiation therapy. One day, he suddenly had abdominal pain and vomiting, and was diagnosed as bowel perforation based on computed tomography. He was managed conservatively by nasogastric suction and antibiotic course. (Case 2) A 62-year-old man diagnosed as metastatic renal cell cancer began immunotherapy soon after undergoing radical nephrectomy in Dec., 2006. Although he was started on oral sorafenib (800 mg/day) in July, 2008, metastatic foci enlarged after 18 months. He was then changed to sunitinib (50 mg/day). Sunitinib had immediate and long-lasting effect on the cancer for about 10 months, but he was then admitted to our hospital for pleural effusion. While under treatment for thoracic cavity drainage, he experienced upper abdominal pain and was diagnosis as bowel perforation based on computed tomography. He underwent emergency laparotomy. Molecular target drugs such as sorafenib and sunitinib have serious adverse effects. Bowel perforation is rare, but among those adverse effects. It should be remembered that caution is required for long-term use or combined radiation therapy and NSAIDs with molecular target drug.

[PSA bounce after brachytherapy with permanent seed implantation for prostate cancer].

PURPOSE: To evaluate prostate specific antigen (PSA) bounce that may occur as a time PSA rise phenomenon during follow up period after brachytherapy (BT) with permanent seed implantation for prostate cancer. (Materials and methods) Seven hundred and forty-six patients had undergone BT from November 2003 to April 2007 in a single institute, and of 130 patients who did not receive hormone therapy and had minimal 3-year follow up are analyzed. PSA bounce was defined as a rise of at least 0.4 ng/ml with spontaneous return to pre-bounce level or lower. RESULT: Among the 130 patients, 40 patients (30.8%) developed PSA bounce, and median time to PSA bounce was 18 months after the BT. With univariate analysis, younger patients (P = 0.027) and larger prostate (P = 0.030) had statistically significant correlation with PSA bounce. With multivariate analysis, younger patients were identified as only independent factor for predicting PSA bounce. Eight patients out of 130 patients (6.2%) triggered the Phoenix definition (nadir + 2 ng/ml) of PSA failure, however, clinical failure was seen only in 3 patients, and other 5 patients were considered as PSA bounce. CONCLUSION: PSA bounce is likely to occur in younger patients within 3 years after BT. It is clinically important to distinguish PSA bounce from PSA failure during following period after BT.